http://emedicine.medscape.

com/article/1104977-overview#a0104
Dermatologic Manifestations of Leprosy
Felisa S Lewis, MD
Updated: Apr 9, 2014
Pathophysiology
Leprosy is not a highly infectious disease. The principal means of
transmission is by aerosol spread from infected nasal secretions to
exposed nasal and oral mucosa. Leprosy is not generally spread by means
of direct contact through intact skin, although close contacts are most
vulnerable.
However, in 2011, a unique strain of M leprae was genotyped in both
humans and wild armadillos infected in the southern United States,
suggesting a direct means of transmission. Several people had distinct
contact with armadillos, including hunting, cooking, or eating armadillos. [2]
The incubation period for leprosy is 6 months to 40 years or longer. The
mean incubation period is 4 years for tuberculoid leprosy and is 10 years
for lepromatous leprosy.
The areas most commonly affected by leprosy are the superficial
peripheral nerves, skin, mucous membranes of the upper respiratory
tract, anterior chamber of the eyes, and the testes. These areas tend to
be cool parts of the body. Tissue damage depends on the degree to which
cell-mediated immunity is expressed, the type and extent of bacillary
spread and multiplication, the appearance of tissue-damaging
immunologic complications (ie, lepra reactions), and the development of
nerve damage and its sequelae.
M leprae is an obligate intracellular, acid-fast, gram-positive bacillus with
an affinity for macrophages and Schwann cells. For Schwann cells in
particular, the mycobacteria bind to the G domain of the alpha-chain of
laminin 2 (found only in peripheral nerves) in the basal lamina, causing
demyelination. Their slow replication within the Schwann cells eventually
stimulates a cell-mediated immune response, which creates a chronic
inflammatory reaction. As a result, swelling occurs in the perineurium,
leading to ischemia, fibrosis, and axonal death. In vivo, M leprae has also
been demonstrated to reprogram Schwann cells to de-differentiate into
mesenchymal stem cells, which may explain the spread of bacteria to
other non-neural tissues.[3]
The genomic sequence of M leprae was only completed within the last few
years. One important discovery is that although it depends on its host for
metabolism, the microorganism retains genes for the formation of a
mycobacterial cell wall. Components of the cell wall stimulate a host
immunoglobulin M antibody and cell-mediated immune response, while
also moderating the bactericidal abilities of macrophages.
More recent research showed that M leprae also induces lipid droplet
accumulation in macrophages and Schwann cells, with an increase in
adipophilin/adipose differentiation-related protein (ADRP). ADRP opposes
the action of hormone-sensitive lipase (HSL), which degrades lipids.
Infected cells from slit-skin smears in lepromatous leprosy correlate with
the findings, with expression of ADRP high and HSL low or undetectable.[4]

The strength of the host's immune system influences the clinical form of
the disease. Strong cell-mediated immunity (interferon [IFN]-gamma,
interleukin [IL]2) and a weak humoral response results in mild forms of
disease, with a few well-defined nerves involved and lower bacterial loads.
A strong humoral response (IFN-beta, IL-4, IL-10) but relatively absent cellmediated immunity results in lepromatous leprosy, with widespread
lesions, extensive skin and nerve involvement, and high bacterial loads.
Therefore, a spectrum of disease exists such that cell-mediated immunity
dominates in mild forms of leprosy and decreases with increasing clinical
severity. Meanwhile, humoral immunity is relatively absent in mild disease
and increases with the severity of disease. T regulatory cells also appear
to suppress the normal immune response.
Toll-like receptors (TLRs) may also play a role in the pathogenesis of
leprosy.[5] M leprae activates TLR2 and TLR1, which are found on the
surface of Schwann cells, especially with tuberculoid leprosy. Although this
cell-mediated immune defense is most active in mild forms of leprosy, it is
also likely responsible for the activation of apoptosis genes and,
consequently, the hastened onset of nerve damage found in persons with
mild disease. Alpha-2 laminin receptors found in the basal lamina of
Schwann cells are also a target of entry for M leprae into these cells, while
activation of the ErbB2 receptor tyrosine kinase signaling pathway has
been identified as a mediator of demyelination in leprosy.[6]
The activation of macrophages and dendritic cells, both antigenpresenting cells, is involved in the host immune response to M leprae. IL1beta produced by antigen-presenting cells infected by mycobacteria has
been shown to impair the maturation and function of dendritic cells. [7]
Because bacilli have been found in the endothelium of skin, nervous
tissue, and nasal mucosa, endothelial cells are also thought to contribute
to the pathogenesis of leprosy. Another pathway exploited by M leprae is
the ubiquitin-proteasome pathway, by causing immune cell apoptosis and
tumor necrosis factor (TNF)alpha/IL-10 secretion.[8]
Research continues to explore the pathophysiology of leprosy, with the
goal of identifying early markers of disease and new targets for treatment.
The most current investigations focus on interferons,[9] the vitamin D
dependent antimicrobial pathway,[10] and NOD2-mediated signaling
pathways,[11, 12] as well as the role of T regulatory cells, Th-17/IL-17a/IL-17F
cytokines, CD163, and galectin-3.[4]
A sudden increase in T-cell immunity, particularly in the Th1 pattern, is
responsible for type I reversal reactions. TLR2 and TLR4 have also been
implicated.[4] Type II reactions result from activation of TNF-alpha and the

deposition of immune complexes in tissues with neutrophilic infiltration

and from complement activation in organs. One study found that
cyclooxygenase 2 was expressed in microvessels, nerve bundles, and
isolated nerve fibers in the dermis and subcutis during reversal reactions.
[13]
Th-17 cytokines, cortisol levels, CXC ligand 10 and matrix
metalloproteinases may also have a role in both type I and II reactions